ABSTRACT Purpose and
We have been investigating genes involved in pulmonary carcinogenesis by examining gene expression profiles of non-small-cell lung cancers to identify molecules that might serve as diagnostic markers or targets for development of new molecular therapies. A gene encoding ADAM8, a disintegrin and metalloproteinase domain-8, was selected as a candidate for such molecule. Tumor tissue microarray was applied to examine expression of ADAM8 protein in archival lung cancer samples from 363 patients. Serum ADAM8 levels of 105 lung cancer patients and 72 controls were also measured by ELISA. A role of ADAM8 in cellular motility was examined by Matrigel assays.
ADAM8 was abundantly expressed in the great majority of lung cancers examined. A high level of ADAM8 expression was significantly more common in advanced-stage IIIB/IV adenocarcinomas than in adenocarcinomas at stages I-IIIA. Serum levels of ADAM8 were significantly higher in lung cancer patients than in healthy controls. The proportion of the serum ADAM8-positive cases defined by our criteria was 63% and that for carcinoembryonic antigen was 57%, indicating equivalent diagnostic power of these two markers. A combined assay using both ADAM8 and carcinoembryonic antigen increased sensitivity because 80% of the lung cancer patients were then diagnosed as positive, whereas only 11% of 72 healthy volunteers were falsely diagnosed as positive. In addition, exogenous expression of ADAM8 increased the migratory activity of mammalian cells, an indication that ADAM8 may play a significant role in progression of lung cancer.
Our data suggest that ADAM8 should be useful as a diagnostic marker and probably as a therapeutic target.

[Show abstract][Hide abstract]ABSTRACT:
The transmembrane ADAM8 (A Disintegrin And Metalloproteinase 8) protein is abundantly expressed in human breast tumors and derived metastases compared to normal breast tissue, and plays critical roles in aggressive Triple-Negative breast cancers (TNBCs). During ADAM8 maturation, the inactive proform dimerizes or multimerizes and autocatalytically removes the prodomain leading to the formation of the active, processed form. ADAM8 is a glycoprotein, however, little was known about the structure or functional role of these sugar moieties. Here, we report that in Estrogen Receptor (ER)α negative, but not positive, breast cancer cells ADAM8 contains N-glycosylation, which is required for its correct processing and activation. Consistently ADAM8 dimers were detected on the surface of ERα negative breast cancer cells but not on ERα positive ones. Site-directed mutagenesis confirmed four N-glycosylation sites (N67, N91, N436 and N612) in human ADAM8. The N67 and N91 prodomain sites contained high mannose, whereas complex type N-glycosylation was observed on N436 and N612 in the active and remnant forms. The N91 and N612 sites were essential for its correct processing and cell surface localization, in particular its exit from the Golgi and endoplasmic reticulum, respectively. The N436Q mutation led to decreased ADAM8 stability due to enhanced lysosomal degradation. In contrast, mutation of the N67 site had only modest effects on enzyme stability and processing. Thus, N-glycosylation is essential for processing, localization, stability and activity of ADAM8.

[Show abstract][Hide abstract]ABSTRACT:
A disintegrin and metalloprotease 8 (ADAM8) has been reported to be associated with various malignancies. However, no studies have examined ADAM8 association in colorectal cancer (CRC). The aim of this study was to investigate the expression and function of ADAM8 in CRC.

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